Amyloidosis Flashcards
What is amyloidosis?
Amyloidosis is a disorder of ____ in which normally soluble proteins are deposited as ____ in ____, which may be __ or __, presents subclinical or diverse array of clinical manifestation. Organ dysfunction is related to __, __ and ____
At least __ human precursor proteins can form amyloid
Rudolph Virchow coined the term amyloid (starch-like) because of the reaction of material similar to cellulose when exposed to __ and __. And the term retained despite recognition of its proteinaceous nature.
Abnormal protein folding
Insoluble proteinaceous material
In tissue extracellular matrix
Localised or systemic
Location, quantity, rate of deposition
30
Iodine and sulfuric acid
Describe the structure of amyloid
Amyloid deposits are _______, which aggregate laterally to form __.
Polypeptide chains oriented perpedicularly to long axis of fibril forming __
Other forms of amyloid include: (3)
Thin, non-branching protein fibrils
Fibrils aggregate laterally to form fibres
Beta pleated sheet conformation
Other amyloids: SAP, GAGs, apolipoproteins (E, J)
Amyloid on light microscopy
Without staining - homogenous, amorphous, hyaline extracellular material
H&E - eosinophilic
Crystal violet - metachromatic
Congo-red - homogenous (beta pleated sheet) with apple green birefringence on polarised microscopy
Origin of amyloid and pathogenesis of amyloid deposition
Amyloids are derived from intact protein or fragment of larger precursor molecule.
Predisposing factors for deposition:
1. Sustained high concentratn of normal proteins (amyloid A in chronic flammation, B2M in renal failure)
2. Exposure to weakly amyloidogenic protein over prolonged period (Beta protein in Alzheimers)
3. Acquired protein with amyloidogenic structure (monoclonal Ig ligh chain in AL amyloid)
4. Inherited variant protein with amyloidogenic structuer (TTR, others)
Amyloidogenic precursor proteins misfold, seed, aggregate and deposit into tissues
Once deposited, amyloid resists proteolysis and phagocytosis
Classification of amyloidosis
- By major protein component
- Specific immunohistochemical staining
What is systemic AL amyloidosis (formerly primary amyloidosis)?
Protein deposition from immunoglobulin light chain fragments
Spectrum of disease:
- Myeloma associated malignant clone of plasma cells
- Small, non-proliferative plasma cells (immunocyte dyscrasia)
Clinical presentation of systemic AL amyloidosis
Non-specific symptoms
1. Fatigue (54%)
2. Weight loss (42%) - profound
3. Pain - peripheral neuropathy (10%), CTS (20%)
4. Purpura (16%)
5. Gross bleeding (8%)
Specific organ involvement:
1. Oedema - nephroticsyndrome
2. Dyspnoea and oedema - restrictive cardiomyopathy
3. Abdominal discomfot - hepatosplenomegaly
4. Seronegative arthropathy resembling RA
5. Painful paresthesias with peripheral neuropathy
6. Orthostasis
7. Syncope
8. Impotence
9. Gut dysmotility - autonomic neuropathy
Examination findings of systemic AL amyloidosis
- Oedema
- Hepatomegaly
- Macroglossia - tongue firmness, dental indentations
- Purpura - upper chest, neck, face, eyelid
- Eyelid pinching purpura
- Raccoon eyes sign - Carpal tunnel syndrome and claw hand
- Tender sensory polyneuropathy
- Arthropathy (shoulder pad sign)
- Nail dystrophy
- Lymphadenopathy
- Submandibular enlargement
Clinical syndromes of systemic AL amyloidosis
- Nephrotic syndrome (commonest)
- Serum/urine electrophoresis and IF - monoclonal protein - Congestive heart failure (1/3 patients)
- cMRI 90% sensitive - amyloid deposit in heart - Peripheral neuropathy
- Autonomic neuropathy (orthostatic hypotension, gastric atony)
- CTS (claw hand)
- Hepatic disease
What clues are alarming for hepatic amyloidosis?
- Proteinuria (high association with concurrent nephrotic syndrome)
- Howell-Jolly bodies in PBF (hyposplenism)
- Hepatomegaly > 15cm out of proportion to LFT
- Elevated ALP > 1.5x upper limit
Characteristic findings in amyloid cardiomyopathy
- Elevated NTproBNP, troponin - predictors of poor survival if do not decrease with therapy
(Normal levels exclude cardiac amyloid) - ECG - generalised voltage reduction
- TTE - restrictive cardiomyopathy
- Symmetric thickening of LV wall > 12mm or thickening of interventricular septum > 6mm
- Hypokinesis (silent infarct)
- Myocardial sparkling echogenicity - Cardiac MRI - delayed subendocardial gadolinium enhancement
Amyloidosis as a great mimicker of rheumatic diseases
- Temporal arteritis
- Claudication of extremities and jaw - Seronegative RA
- Lack of inflammation
- Frequent hip and shoulder involvement, pericarticular amyloid infiltration, enlargement of pelvic or shoulder girdle (shoulder pad sign)
- Synovial fluid analysis - amyloid deposits - Polymyositis
- Pseudohypertrophy of muscles
- Amyloid infiltration of muscles
How does amyloid cause bruising and bleeding?
- Amyloid deposit in blood vessels weakens vessel wall and easy bruising
- Amyloid associated acquired factor X deficiency
- Amyloid fibrils and factor X bound together
What is systemic AA amyloidosis (formerly secondary/reactive amyloidosis)?
Deposition of SAA fragments that forms amyloid fibrils, as a result of chronic inflammatory disorders (infectious, neoplastic, rheumatic, heritable periodic fever syndromes)
Common features: renal involvement, hepatosplenomegaly
Less common: cardiac, nerve
(To note that 7% patients with AA amyloidosis have no clinically obvious chronic inflammatory disease, or undiagnosed autoinflammatory syndrome/Castleman syndrome)
Untreated chronic infection - rapidly progressive
Chronic inflammatory - slow progression
What are the conditions commonly associated with systemic AA amyloidosis?
A. Infections
Tuberculosis
Leprosy
Chronic pyelonephritis
Bronchiectasis
Osteomyelitis
Paraplegia complications
Parenteral drug abuse
B. Neoplasms
Hodgkin disease
Non-Hodgkin lymphoma
Renal cell carcinoma
Melanoma
Cancers of GI tract, genitourinary, lung
C. Rheumatic
RA
Juvenile idiopathic arthritis
Ankylosing spondylitis
(With treatments, frequency reduced <1%)
What other amyloidoses occur commonly in elderly?
- Senile amyloidosis - transthyretin amyloid (ATTR) deposition in over 70 years old.
- Aβ protein amyloidosis - Alzheimer’s, CAA
What is localised AL amyloidosis and its presentation?
Localised deposits resembling tumour
Common sites: lung, skin, larynx, eye, bladder
Focal infiltrate of monoclonal B cells producing amyloidogenic light chains
Progression to systemic disease or melanoma is exceedingly rare
Surgical or laser excision can be performed
Localised endocrine amyloidosis
- ACal (calcitonin) - medullary carcinoma of the thyroid
- AANF (atrial natriuretic factor) - isolated atrial amyloid
- AIAPP (islet amyloid polypeptide) - type 2 diabetes mellitus, insulinoma
- APro (prolactin) - local amyloid in prolactinomas
Dialysis-related amyloidosis
β2-microglobulin amyloid deposits (invariant chain of MHC class I molecule) in patients on haemodialysis for at least 5 years
80% dialysis > 15 years have amyloidosis
Mainly presents with osteoarticular complaints, CTS, shoulder pad sign.
Spondyloarthropathy with intervertebral disc destruction mimicking infection
Paravertebral erosions
Cystic bone changes
Rarely involves skin, GI tract, heart
Synovial fluid with Congo red staining - B2M amyloid deposits
Treatment: renal transplant
Hereditary amyloidosis
ATTR variant
Autosomal dominant disease
Peak onset 20 and 60 years
Clinical features similar to AL amyloidosis but with strong family history
(Sporadic ATTR mutation may occur)
Treatment: liver transplant - removes source of variant TTR production
Death within 5-15 years without transplant
Emerging treatment:
1. Tafamidis meglumine - binds and stabilises TTR tetramers preventing fibril formation/deposition
2. Diflunisal (NSAID)
3. RNA targeted therapies - patisiran, inotersen
Other hereditary amyloidosis: cystatin C, gelsolin, lysozyme, fibrinogen A alpha chain, apolipoprotein A-I and A-II
Diagnosis and investigation of amyloidosis
- Tissue biopsy
- Hyaline material on light microscopy
- Congo-red stain - apple green birefringence on polarised microscopy
- Thioflavine T stain - intense yellow-green fluorescence
- IF - characterises subunit type (AA, ATTR)
(See selection of tissues in subsequent card) - Serum and urine protein electrophoresis and immunofluorescent - TRO plasma cell dyscrasia
- DNA analysis for amyloidogenic variant protein if suspecting hereditary amyloidosis
- MRI or ultrasound of joints (shoulder)
- Rotator cuff > 8mm thickness with echogenic deposits - Radiolabeled I-123 SAP scintigraphy
- AL and AA 90%; ATTR 48%
- Establish extent of disease, monitor response to treatment
Tissue selection for biopsy
- Selection of screening tissues:
- Abdominal fat pad
- Bone marrow
- Rectal mucosa
- Salivary gland
- Skin
(15% patients with systemic AL amyloidosis will have both a negative abdominal fat pad and bone marrow biopsy)
- Favourable organ for biopsy
- Kidney
- Carpal ligament
- Liver
- Sural nerve
- Skin
(Risk of bleeding may be substantial)
Treatment of systemic AL amyloidosis
- Melphalan and dexamethasone regimen
- High dose chemotherapy and autologous peripheral blood stem cell transplantation
- Bortezomib and lenalidomide regimen
- Dartumumab (anti-CD38) - eliminates clonal B cells
- Miridesap (SAP binder)
- Dezamizumab (Ab against SAP)
Avoid digitalis, CCB and beta blockers in amyloid cardiomyopathy
Prognosis in systemic AL amyloidosis
Median survival: 12 - 15 months
Reduced significantly with multiple myeloma
Commonest cause of death: cardiomyopathy
Heart failure - prognosis of 6 months
Best prognosis: isolated peripheral neuropathy
Prognosis of 56 months
Increased serum creatinine, failure of serum/urine free light chains to decrease - poor prognosis
Treatment and prognosis of AA amyloidosis
Mobilization and clearance of amyloid deposits are possible and are best recognized for patients with AA
- Control underlying inflammation
- Prophylactic colchicine
- Surgical treatment of osteomyelitis
- Aggressive Crohn’s disease management
- Monitor SAA levels for success of therapy
- Anti-amyloid immunotherapy (ongoing trials)
Prognosis:
40-60% 5 to 10-year survival in unsuppressed inflammation
Treatment of ATTR amyloidosis
Tafamidis
